||CRISPR-Cas9 molecular scissors: a bit too sharp?
CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations.
Biotherapy team, U1035.
Cullot et al., Nat Commun. 2019
We described that CRISPR-Cas9-nuclease induces high chromosomal toxicity, with megabase-scale chromosomal truncations and duplication exactly starting at CRISPR-Cas9 nuclease DSB. We extend our data from cell lines to primary cells with higher impact for future CRISPR clinical application. We demonstrate that this chromosomal truncation risk is p53-dependent in primary cells. Taken together, this report raises the biosafety issue of CRISPR-Cas9 medical applications, in the same time of several ongoing clinical trials. Even worse, Dr. Jiankui He used CRISPR-Cas9 nuclease to alter the genome of human embryos prior to uterus implantation. It seems to us that the scientific community has to be warned of chromosomal deletion risk. Interestingly, we found that, by contrast to nuclease, single CRISPR-Cas9 nickase approach strongly limit this risk.
This work was supported by the Association Française contre les Myopathies Grant # 20957, and the Agence de Biomédecine.
CRISPR-Cas9 genome editing inducesmegabase-scale chromosomal truncationsGrégoire. Cullot1,2, Julian Boutin1,2,3, Jérôme Toutain4, Florence Prat1,2, Perrine Pennamen4, Caroline Rooryck4, Martin Teichmann1,5, Emilie Rousseau1,5, Isabelle Lamrissi-Garcia1,2, Véronique Guyonnet-Duperat2,6, Alice Bibeyran2,6, Magalie Lalanne1,2, Valérie Prouzet-Mauléon1,7, Béatrice Turcq1,7, Cécile Ged1,2,3,8, Jean-Marc Blouin1,2,3,8, Emmanuel Richard1,2,3,8, Sandrine Dabernat1,2,3, François Moreau-Gaudry1,2,3,6,8 & Aurélie Bedel1,2,3,8. Nat Commun. 2019
1Univ. Bordeaux, 33000 Bordeaux, France. 2INSERM U1035, Biotherapy of genetic diseases, inflammatory disorders and cancers, 33000 Bordeaux, France. 3Biochemistry Laboratory, CHU Bordeaux, 33000 Bordeaux, France. 4Medical genetic laboratory, CHU Bordeaux, 33000 Bordeaux, France. 5UMR 5320,INSERM U1212, ARNA Laboratory, 33000 Bordeaux, France. 6Vectorology Platform, 33000 Bordeaux, France. 7INSERM U1218, ACTION, 33000 Bordeaux, France. 8Laboratory of excellence, GR-Ex, Imagine institute, 75015 Paris, France. These authors contributed equally: Grégoire Cullot, Julian Boutin, François Moreau-Gaudry, Aurélie Bedel.